Cartilage disorders broadly refer to diseases characterized by degeneration of metabolic abnormalities in the connective tissues which are manifested by pain, stiffness and limitation of motion of the affected body parts. These disorders can be due to pathology or can be the result of trauma or injury. Among others, cartilage disorders include osteoarthritis (OA) and cartilage injury (including sports injuries of cartilage and joints, and surgical injuries such as microfracture(s)). Mature cartilage has limited ability to repair itself, notably because mature chondrocytes have little potential for proliferation and due to the absence of blood vessels. In addition, cartilage is not well nutrified and has a low oxygen pressure. Replacement of damaged cartilage, in particular articular cartilage, caused either by injury or disease is a major challenge for physicians, and available surgical treatment procedures are considered not completely predictable and effective for only a limited time. Therefore, the majority of younger patients either do not seek treatment or are counseled to postpone treatment for as long as possible. When treatment is required, the standard procedure is age-dependent and varies between total joint replacement, transplantation of pieces of cartilage or marrow stimulating technique (such as microfracture). Microfracture is a common procedure that involves penetration of the subchondral bone to stimulate cartilage deposition by bone marrow-derived stem cells. However, it has been shown that this technique does not sufficiently repair the chondral defect and the new cartilage formed is mainly fibrocartilage, resulting in inadequate or altered function and biomechanics. Indeed, fibrocartilage does not have the same durability and may not adhere correctly to the surrounding hyaline cartilage. For this reason, the newly synthesized fibrocartilage may break down more easily (expected time frame: 5-10 years).
For patients with osteoarthritis, non-surgical treatment consists notably of physical therapy, lifestyle modification (e.g., reducing activity), supportive devices, oral and injected drugs (e.g., non-steroidal anti-inflammatory drugs), and medical management. Once these treatments fail, surgery, such as joint replacement, is the main option for the patients. Such an option can provide a reduction in symptoms that is generally only short lived. Tibial or femoral osteotomies (cutting the bone to rebalance joint wear) may reduce symptoms, help to maintain an active lifestyle, and delay the need for total joint replacement. Total joint replacement can provide relief for the symptom of advanced osteoarthritis, but generally requires a change in a patient's lifestyle and/or activity level.
At that time, drug treatments on the market are mainly directed to pain relief. There is not yet a commercially available treatment that restores cartilage damage (see Lotz, 2010).
Fibroblast Growth factor 18 (FGF-18) is a member of the FGF family of proteins, closely related to FGF-8 and FGF-17. It has been shown that FGF-18 is a proliferative agent for chondrocytes and osteoblasts (Ellsworth et al., 2002; Shimoaka et al., 2002). FGF-18 has been proposed for the treatment of cartilage disorders such as osteoarthritis and cartilage injury, either alone (WO2008/023063) or in combination with hyaluronic acid (WO2004/032849).
Sprifermin, which is a truncated form of human FGF-18, is being investigated in clinical trials for treatment of both osteoarthritis and cartilage injury (for more details see for instance NCT01033994, NCT00911469 and NCT01066871). The current dosing regimen for sprifermin is once weekly for 3 weeks (one treatment cycle), the drug being administered via intra-articular injections. This treatment cycle can be repeated. This dosing regimen has been described in WO2008023063.
At that time, OA and cartilage injury treatments with FGF-18, during clinical trials, are provided to patients without predictive information on the response, i.e., without knowledge on whether the treatment will likely be highly effective, moderately effective or show only little or no effect. Currently, numerous treated patient populations exhibit an intermediate/high response to treatment according to the WOMAC scores with sprifermin after at least one treatment cycle, however, others either do not respond to said treatment or respond while presenting high WOMAC scores compared to control.
Here we describe for the first time genetic markers that are associated with the quality of the clinical response to treatment of cartilage disorders such as OA, cartilage injury or microfracture(s) with FGF-18. Such markers are useful for identifying, through genetic screening prior to the treatment, subgroups of patients that are more likely to exhibit a particular response to treatment with FGF-18, such as a very good clinical response to treatment with FGF-18, or on the contrary those for whom the therapy may fail. Knowledge of the type of clinical response of a patient to treatment can be used to optimize therapy or select therapy, such as selecting treatment with FGF-18 as a first line therapy or adapting the dosing regimen. Such information will be clinically useful for the medical management of cartilage disorders, such as OA/cartilage injury, in patients. For example, if an individual with OA or cartilage injury is known to be at increased risk for not responding to the FGF-18 treatment, the physician may exclude said patient from the FGF-18 treatment. In addition, such predictive information may also be clinically useful to guide decisions on the dosing regimen.